PATHOGENESIS OF BACTERIAL INFECTION
The microorganism should be found in all
(from Dr. Lagamayo’s ppt)
• initiation of infectious process
• mechanisms that lead to the development
of signs and symptoms of disease
CHARACTERISTICS OF PATHOGENIC BACTERIA:
• Transmissibility
• Adherence to host cells
• Invasion of host cells and tissues
• Toxigenicity
• Ability to evade the host’s immune system
(“escape mechanisms)
Definition of Terms:
1. Adherence (adhesion, attachment) –
process by w/c bacteria stick to the host
cell surfaces
2. Carrier – a person or animal with
asymptomatic infection that can be
transmitted to another susceptible person
or animal
3. Infection – multiplication of an infectious
agent within the body
4. Invasion – a process whereby bacteria,
animal parasites, fungi, and viruses enter
host cells or tissues and spread in the
body
5. Nonpathogen – microorganism that does
not cause disease (normal flora)
6. Opportunistic pathogen – capable of
causing disease only when host’s
resistance is impaired
Ex. E.coli, Pseudomonas spp.,
Stenotrophomona maltophilia
7. Pathogen – capable of causing disease
Ex. Mycobacterium tuberculosis, Yersinia
pestis
8. Pathogenicity – ability to cause disease
9. Toxigenicity – produce toxin that
contributes to the development of disease
10. Virulence – quantitative ability of an agent
to cause disease
Other Epidemiologic Terms:
1. Etiologic agent - microorganism
responsible for causing infection or
disease
2. Common source – etiologic agent
responsible for an epidemic or outbreak,
originates from a single source or reservoir
3. Incidence – number of diseased or
infected persons in a population
4. Prevalence - % diseased in a given pop’n
at a given time
5. Endemic – disease constantly present at
some rate of occurrence in a particular
location
6. Epidemic – larger than normal number of
diseased in a particular region
7. Pandemic – epidemic spanning the world
8. Outbreak – larger than normal number of
diseased that occurs over a relatively
short period of time
9. Nosocomial infection – infection acquired
from hospital
10. Strain typing – relatedness of organisms to
one another during a particular outbreak
or epidemic
11. Surveillance – epidemiologic investigation
12. Vector – carrier of etiologic agent
13. Vehicle – non-living entity contaminated
by etiologic agent
Koch’s Postulate
1.
cases of the disease in question, and its
distribution in the body should be in
accordance with the lesions observed
2. The microorganisms should be grown in pure
culture in vitro for several generations
3. When such pure culture is inoculated into
susceptible animal species, the typical
disease must result
4. The microorganism must again be isolated
from such experimentally produced disease
*Organisms that do not meet Koch’s
postulate:
o Cannot be grown in culture, only in animal
model:
Treponema pallidum (syphilis)
Mycobacterium leprae (leprosy)
o Can be grown only in culture:
Neisseria gonorrhea (gonorrhea)
Molecular Koch’s Postulate
• study of genes assoc. with virulence
• PCR – used to amplify microorganism-
specific nucleic acid sequences
• Ex. Whipple’s disease (Tropheryma
whipplei), Bacillary angiomatosis
(Bartonella henselae), Human monocytic
ehrfichiosis (Ehrlichia chaffeensis),
Hantavirus pulmonary syndrome (Sin
Nombre virus), Kaposi’s sarcoma (human
herpes virus 8)
Molecular Koch’s Postulate
1. Phenotype or property under investigation
should be significantly associated with
pathogenic strains of a species and not with
nonpathogenic strains
2. Specific activation of the genes assoc with
the suspected virulence trait should lead to
measurable decrease in pathogenicity or
virulence
3. Reversion or replacement of the mutated
gene with the wild-type gene should lead to
restoration of pathogenicity or virulence.
MOLECULAR GUIDELINES FOR ESTABLISHING
MICROBIAL DISEASE CAUSATION:
1. Nucleic acid sequence of a putative
pathogens should be present in most
cases of an infectious disease
2. Nucleic acid sequence of a putative
pathogen should be absent from most
healthy controls. If ever, it should be
present in lower copy numbers
3. Copy number of pathogen-assoc. nuclei
acid sequence should decrease or become
undetectable with resolution of the
disease and should increase with relapse
or recurrence of disease
4. The presence of pathogen-assoc. nucleic
acid sequence in healthy subjects should
help predict the subsequent development
of disease
5. The nature of pathogen inferred from
phylogenetic analysis of its nucleic acid
sequence should be consistent with the
known biologic characteristics of closely
related organisms and the nature of the
disease
6. A dose-response relationship between
pathogen-associated nucleic acid
sequence and pathology should be
evident
7. The sequence-based findings should be
reproducible
TRANSMISSION OF INFECTION
• Bacteria adapt to the environment to:
o ensure their survival
o enhance the possibility of transmission
– asymptomatic infection or mild
disease (Ex. Hepa B)
• Some bacteria exist primarily in animals
and incidentally infect humans
o Salmonella in eggs and
Campylobacter in milk)
• Some bacteria produce inadvertent
infection of humans
o Yersinia pestis causing plague
<rodents—fleas—man>
o Bacillus anthracis causes anthrax –
lives in the environment, occasionally
infects animals transmitted to humans
by contaminated raw hair
• Inadvertent infections
o Clostridium spp. – ubiquitous in the
environment and are transmitted to
humans by ingestion (C. perfringens &
C. botulinum) or when wounds are
contaminated by soil (C. perfringens &
C. tetani)
• Disease manifestations of microorganisms
often promote transmission of these
agents
o Vibrio cholerae, E. coli (diarrhea),
Mycobacterium tuberculosis (cough)
TRANSMISSION OF INFECTION IN HUMANS
• Person to person contact through hands
(nosocomial infections)
Ex. Staphylococcus aureus
• Most common portals of entry (mucous
membrane with the skin)
o Respiratory tract (upper and
lower)
o GI tract
o Genitourinary tract
• Cuts, burns, injuries
INFECTIOUS PROCESS
*Streptococcus pneumoniae in the nasopharynx
may be aspirated into the lungs (aspiration
pneumonia) resulting in bacteremia in 10-20% of
individuals affecting the CSF (meninges), heart
valves and joint spaces
HOST-MICROORGANISM INTERACTIONS
Encounter and entry
Pathogen encounters and colonizes host surface
Colonization and entry
Pathogen multiplies and breaches host surface defenses
Invasion and dissemination
Pathogen invades deeper tissues and disseminates,
encounters inflammatory and immune responses
Outcome
Pathogen completes cycle:
- leaves host
- destroys host
- remains in latent state
- is destroyed by host
INFECTION-DISEASE STAGES
Incubation stage
No signs or symptoms
Prodromal stage
First signs and symptoms
Pathogen may be highly communicable
Clinical stage
Peak of characteristic signs and symptoms of infection or
disease
Stage of decline
Condition of host deteriorates possibly to death or signs
and symptoms begin to subside as host condition
improves
Convalescent stage
Full recovery of surviving host or chronic infection
develops or death
SIGNS AND SYMPTOMS OF INFECTION &
INFECTIOUS DISEASE
• General or localized aches and pains
• Headaches and fever
• Swollen lymph nodes
• Rashes
• Redness and swelling
• Cough and sneezes
• Congestion of nasal and sinus passages
• Sore throat
• Nausea and vomiting
• Diarrhea
MICROBIAL STRATEGIES FOR SURVIVING
INFLAMMATION
• Avoid killing by phagocytes (PMNs,
Monocytes and Macrophages)
o Inhibit ability of phagocyte to ingest
by producing capsule
o Avoid phagocyte mediated killing by:
 Inhibiting phagosome lysosome
fusion
 Being resistant to destructive
agents (ex. Lysozyme released by
lysosomes)
 Actively and rapidly multiplying
within the phagocyte
• Avoid effects of the complement system
o Use capsule to hide surface molecules
that would otherwise activate the
complement system
o Produce substances that inhibit the
processes involved in complement
activation
o Produce substances that destroy
specific complement proteins
MICROBIAL STRATEGIES FOR SURVIVING THE
IMMUNE SYSTEM
• Pathogen multiplies and invades so
quickly that damage to host is complete
before immune response can be fully
activated (influenza)
• Pathogen invades and destroys cells
involved in the immune response (HIV)
• Pathogen survives, unrecognized, in host
cells and avoids detection by immune
system
• Pathogen covers its antigens with a
capsule so that immune response is not
activated
• Pathogen changes antigens so that
immune system is constantly fighting a
primary encounter
• Pathogen produces enzymes (proteases)
that directly destroy or inactivate
antibodies.
CLONAL NATURE OF BACTERIAL PATHOGENS • Excreted by living cells; ↑ conc. in liquid
• Primary mechanism for exchange of medium
genetic info between bacteria: plasmids or
• Most commonly associated with gram
phages
positive bacteria
• Clonality of organisms:
• Unstable, destroyed at temp. > 60˚ C
o Result of conservation of chromosomal
• Highly antigenic
genes in bacteria
o One or a few clonal types of organism • Converted to antigenic non-toxic toxoids
spread in the world during a period of by formalin, acid, heat etc. (for vaccines
time (epidemic) ex. Tetanus)
o Examples: • Highly toxic; fatal
 Serogroup A meningococcoal • Specific receptors
meningitis in Asia, Middle • Does not produce fever
East, and Africa • Controlled by extrachromosomal
 H. influenzae type b components (ex. plasmids)
 Two clonal types of Bordetella
Endotoxin
pertussis and Salmonella typhi
assoc with disease • Released on bacterial death
• Integral in gram negative bacteria
BACTERIA VIRULENCE FACTORS • Composed of lipopolysaccharide
A. adherence factors complexes (LPS portion of cell envelope)
B. toxins
C. enzymes
• Stable; withstands heat at temp. >60˚ C
D. antiphagocytic Factors • Weakly immunogenic
E. intracellular pathogenicity • Not converted to toxoids
F. antigenic heterogeneity • Moderately toxic
• Specific receptors not found on cells
A. Adherence Factors
• Produces fever (triggers release of IL-1)
• Surface hydrophobicity
• Synthesis directed by chromosomal genes
• Net surface charge
*Effects on host:
• Host cell receptor interactions
o Disseminated intravascular coagulation
o Fever
*Hydrophobicity of bacterial cell surface is directly
proportional to the adherence to the host cell o Activation of complement and immune
systems
Pili – hair like appendages that extend from o Circulatory changes that lead to
bacterial surface hypotension, shock and death

Examples: C. Enzymes
1. E. coli strains have 1 pilus which adhere to 1. Tissue degrading enzymes
epithelial receptors containing D-mannose Lecithinase – C. perfringens
> adherence can be blocked in vitro by Collagenase – C. perfringens
adding D-mannose to the medium Hyaluronidase – Staph., Strep., anaerobes
2. E. coli causing UTI have P pili which attach to a Coagulase – S. aureus
portion of P-blood group Ag(α-D-galatopyranosyl- Streptolysin O, S
(1-4)-β –D-galactopyranoside [GAL-GAL binding Cytolysins: leucocidins, hemolysins
adhesion} 2. IgA1 proteases
3. Streptococcus pyogenes (Group A strep) have N. gonorrhea
fimbriae N. meningitides
> Fimbriae – lipoteichoic acid, Protein F, Protein H. influenza
M S. pneumoniae
> Protein F and lipoteichoic acid- adherence to
buccal epithelial cells
> Fibronectin – act as host cell receptor
molecule D. Antiphagocytic factors
> M protein – anti-phagocytic molecule • Protein A of Staphylococcus aureus binds
to Fc portion of IgG
B. Toxins Ex. Streptococcus pneumoniae
Classification of toxins: N. meningitides
1. Exotoxin – V. cholerae, S. aureus (enterotoxin), S. pyogenes (M protein)
V.parahemolyticus, C. perfringens, C. Botulinum N. gonorrhea (pili)
2. Endotoxin – GND (Enterobacteriaceae)
- lipopolysaccharide (LPS) E. Intracellular pathogenicity
3 main regions : • Mechanisms:
• O-specific polysaccharide 1. avoid entry into phagolysosomes and
• Common core polysaccharide live within the cytosol of phagocytes
• Lipid A with KDO (2-keto-3- 2. prevent phagosome-lysosome fusion
deoxyoctonic acid) and live within the phagosome
- lipooligosaccharide 3. resistance to lysosomal enzymes and
- heat stable survive within the phagolysosome

*peptidoglycan of gram positive bacteria causes

• Ex. Mycobacterium tuberculosis
vascular damage leading to shock Brucella spp.
Legionella spp.
Exotoxin
 • Inside PMN cells, macrophages or
monocytes
F. Antigenic heterogeneity (surface structures)
• The antigenic type of bacteria may be a
marker of virulence
• Examples:
o V. cholerae O antigen type 1 and O
antigen type 139 – produce cholera
toxin
o ≥80 group A streptococcal M protein
types – high incidence of post strep.
glomerulonephritis
o N. meningitides capsular
polysaccharide types A & C area
associated with epidemic meningitis
o Borrelia recurrentis (relapsing fever)
o N. gonorrhea – 3 surface- exposed
antigens that switches forms at a high
rate (LOS, pili, Opa(protein II))
REGULATION OF BACTERIAL VIRULENCE FACTORS
Corynebacterium diptheriae
o The gene for diphtheria toxin is carried on
temperate bacteriophage
o Toxin produced only by strains lysogenized
by the phages
o Enhanced toxin production with low iron
medium
Bordetella pertussis
o Expression of virulence genes is enhanced
when grown at 37˚ C and suppressed
when grown at lower temp
o In the presence of high concentrations of
Mg sulfate or nicotinic acid
Vibrio cholerae
o Expression of cholera toxin:
-higher at pH 6.0 than pH 8.5
- higher at 30˚ C than at 37˚ C
Yersinia pestis
o YOPS – series of yersinia virulence
plasmid-encoded proteins with
antiphagocytic function
o Expressed maximally at 37˚ C in the
absence of calcium
Yersinia enterocolitica
o Motile at 25˚ C, non motile at 37˚ C
Listeria monocytogenes
o Motility enables the bacteria to spread and
multiply in the environment or in the
patient
INVASION OF HOST CELLS and TISSUES
• Invasion – entry of bacteria into the host
cells
- many bacteria produce virulence
factors that influence the host cells
• Toxin production and other virulence
properties are generally independent of
the ability of bacteria to invade cells and
tissues.
Examples:
1. Corynebacterium diphtheria can invade
the epithelium of nasopharynx and cause
symptomatic sore throat even when the C.
diphtheria strains are nontoxigenic
2. Shigella sp. Adhere to host cells in vitro
(HeLa cells- undifferentiated unpolarized
cells from cervical CA)
*adherence causes actin polymerization
in the nearby HeLa cells  pseudopod
formation engulfment of bacteria
*In vivo
Shigella adhere to integrins on the
surface of M cells in Peyer parches. M cells
sample antigens and present them to
macrophages in the submucosa.
Shigella are phagocytosed by M
cells, pass through M cells, escape killing by
macrophages
Ex. Yersinia enterocolitica, Listeria
monocytogenes
3. Legionella pneumophilia
adherence to macrophage formation of
thin, long pseudopod which coils around the
bacteria forming a vesicle (coiling
phagocytosis) bacteria multiplies within
the vesicle
4. Neisseria gonorrhea
pili (primary adhesions)
opacity associated proteins (Opa)
- secondary adhesions to host cells
- some Opa mediates adherence to
PMNs
THE REQUIREMENT FOR IRON
• Bacteria require 0.4-4μmol of iron in order
to grow
• Siderophores (MW 500-1000):
o Small ligands that are specific for
ferric iron and supply iron to the
bacterial cells
o Capture iron
o Produced only under low iron
conditions
o 2 Categories:
a. Catechols (phenolates)
Ex. enterobactin – used
Enterobacteriaceae
-remove iron from transferring
b. Hydroxamates – found in fungi
Ex. Ferrichrome
• The availability of iron affects the
virulence of pathogens
• N. meningitidis – virulence for mice in
increased ≥1000 fold when the bacteria is
exposed under iron-limited conditions
ROLE OF BACTERIAL BIOFILMS
Biofilm
• aggregate of interactive bacteria attached
to a solid surface or to each other,
encased in an exopolysaccharide matrix
• forms slimy coat on solid surfaces and
occurs throughout nature
Human infections associated with biofilm:
• Staph. epidermidis & Staph. Aureus
- central venous catheters
- eye infections (contact and intraocular
lenses)
- dental plaque
• Pseudomonas aeruginosa
- airway infections in cystic fibrosis
Biofilm formation

Colonization of the surface

(flagella, pili, cell division)

Quorum sensing
signals
(acylhomoserin
e lactose
signals) α to
number of

Bacterial change in behavior

(changing activation of genes)
*extracellular polysaccharide production
*alginate production by P. pseudomonas
*genes influence metabolic pathway
*production of virulence factors
*antimicrobial resistance (diffusion
border)

Sarah 07/14/06